The enzyme adenosine deaminase (ADA) catalyzes the irreversible deamination of both adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. Congenital deficiency of ADA results in Severe Combined Immunodeficiency Disease (SCID) and marked lymphopenia. Lack of ADA primarily results in toxicity to lymphocytes, pharmacologic inhibition of ADA may result in a selective chemotherapeutic effect in lymphoproliferative malignancies. We propose to study the clinical and biochemical effects of 2'-deoxycoformycin (2'-dCF), a potent ADA inhibitor, in patients with refractory acute lymphoblastic leukemia or lymphoma. Our plan is to investigate 1) the clinical utility, 2) whether or not we can use in-vitro tests to predict responses, 3) the biochemical consequences of 2'-dCF therapy and how they correlate with lymphocytotoxicity and systemic toxicity, 4) whether systemic toxicity can be predicted, avoided, or reversed, 5) the pharmacology of the drug, and 6) whether it is reasonable to consider adding second agents to improve the therapeutic index of 2'-dCF. We have developed the techniques to follow numerous relevant parameters on a daily basis, including lymphoblast and erythrocyte ADA activity; plasma, urine, and CSF 2'dCF levels; plasma and urinary adenosine and deoxyadenosine concentrations; lymphoblast and erythrocyte nucleoside triphosphate levels; and SOadenosylhomocysteine hydrolase activity. We also plan to do in-vitro tests to explain observations we have recently made, such as the mechanism for ATP depletion associated with dATP accumulation or the mechanism of 2'-dCF inhibition of deoxyadenosine urinary excretion. These studies should enhance our understanding of the mechanism(s) by which lymphoid cells are killed in ADA deficiency and provide a basic foundation for the future use of 2'-deoxycoformycin in malignant lymphoproliferative disease.